Pain relief is of prime importance to anyone treating patients undergoing surgery. Proper pain relief imparts significant physiological and psychological benefits to the patient. Not only does effective pain relief mean a smoother more pleasant postoperative course (e.g., mood, sleep, quality of life, etc.) with earlier discharge from medical/surgical/outpatient facilities, but it may also reduce the onset of chronic pain syndromes (e.g., fibromyalgia, myalgia, etc.).
Pain serves a biological function. It often signals the presence of damage or disease within the body and is often accompanied by inflammation (redness, swelling, and/or burning). In the case of postoperative pain it may be a result of the surgery, or other treatments such as, for example, management of acute pain following burns or non-surgical trauma. The goal for postoperative pain management is to reduce or eliminate pain and discomfort with medication that cause minimum or no side effects.
The site of the surgery has a profound effect upon the degree of postoperative pain a patient may suffer. In general, operations on the thorax and upper abdomen are more painful than operations on the lower abdomen, which in turn are more painful than peripheral operations on the limbs. However, any operation involving a body cavity, large joint surfaces, the spine or deep tissues should be regarded as painful. In particular, operations on the thorax or upper abdomen may produce widespread changes in pulmonary function, an increase in abdominal muscle tone and an associated decrease in diaphragmatic function. The result will be an inability to cough and clear secretions, which may lead to lung collapse and pneumonia. Prolonged pain can reduce physical activity and lead to venous stasis and an increased risk of deep vein thrombosis and consequently pulmonary embolism. In addition, there can be widespread effects on gut and urinary tract motility, which may lead in turn to postoperative ileus, nausea, vomiting and urinary retention. These problems are unpleasant for the patient and may prolong hospital stay. Most patients who experience moderate to severe post-operative pain, post-traumatic pain and burn pain, often require pain control at least in the first 3 days after trauma or surgery.
Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) with not only anti-inflammatory properties, but also analgesic properties similar to opioids although it is not a narcotic. Ketorolac as an NSAID also has antipyretic activities to reduce elevated body temperature.
In general the chemical name of ketorolac is (+/−)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid or 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid. Ketorolac has a molecular weight of 255.27 and exhibits the following general structure:

The major mechanism by which ketorolac exerts its pharmacological effects is by the inhibition of prostaglandin synthesis. In particular, it is believed that the primary action of ketorolac (as all NSAIDs) is to inhibit cyclooxygenase, which is responsible for the biosynthesis of prostaglandins, prostacyclin and thromboxane. Prostaglandins, which are released from virtually all tissues in response to direct trauma or surgery, act to mediate pain and inflammation.
Preoperative administration of ketorolac reduces pain in the immediate post-operative period. Combination therapy with ketorolac and opioids results in a significant 25% to 50% reduction in morphine and fentanyl requirements in the first 1 to 2 post-operative days, and may be accompanied by a reduction in opioid-induced adverse events. In addition, when using ketorolac, some patients experience a more rapid return to normal gastrointestinal function and shorter stay in hospitals as opioids tend to slow bowel function and cause constipation.
Ketorolac's analgesic efficacy in the postoperative setting has been evaluated in patients exhibiting various stages of pain in both hospital inpatients and outpatients. Intramuscular administration of doses of 10-30 mg ketorolac can provide an analgesic efficacy similar to that of intramuscular administration of 6-12 mg of the opioid morphine.
Currently, ketorolac is commercially available for intramuscular (IM), intravenous (IV), subcutaneous (SC) or oral administration, and is indicated for the short-term treatment of moderate to severe pain. The usual parenteral dosage of ketorolac is 10-30 mg every 4 to 6 hours IV or IM with a maximum total daily dose of 90 mg and a maximum duration of therapy of 5 days. For post-operative analgesia, single or multiple doses of intramuscular or intravenous administration of 10-30 mg ketorolac can provide an analgesic efficacy similar 6-12 mg morphine IM or 2-4 mg morphine IV.
Ketorolac has been administered IV for patient-controlled analgesia at a dose of 5 mg/h to provide pain relief similar to that of a morphine dose of 1 mg/h in patients after major abdominal surgery. SC administration of 60-120 mg/day of ketorolac may be beneficial in the treatment of some patients with cancer pain, especially those with a component of pain resulting from bone metastases, and may be accompanied by a concomitant reduction in opioid dosage.
Unfortunately, currently available ketorolac formulations, although effective for treating postoperative pain, require frequent single dose administration every 4 to 12 hours on an as needed basis. Often with the single dose ketorolac dosing, the patient will experience break through pain and anxious “clock-watching” waiting for the next dose in order to provide persistent pain release. These single dose ketorolac formulations are inconvenient and may interfere with the patient's postoperative inpatient and/or outpatient daytime activities and nighttime sleep and recovery.
New ketorolac compositions and methods are needed to prevent, treat or reduce postoperative pain or inflammation. Ketorolac compositions and methods that reliably provide long acting analgesic and anti-inflammatory effects over periods of 3 to 10 days are needed.